ABSTRACT Bacterial pneumonia with or without sepsis is among the most common cause of acute respiratory failure in critically ill patients leading to acute respiratory distress syndrome (ARDS). Despite improvements in supportive care and appropriate antibiotic use, mortality from ARDS remains as high as 40%. Therefore, new innovative therapies are needed. Hyaluronan or hyaluronic acid (HA) is normally synthesized as a high molecular weight (HMW) nonsulfated glycosaminoglycan and is a chief component of the extracellular matrix and critical for maintaining the normal structure of alveolar air-blood barrier. In multiple pulmonary disorders including acute lung injury (ALI), asthma, COPD or pulmonary hypertension, HA undergoes degradation by hyaluronidases, reactive oxygen and nitrogen species and inflammatory mediators. The degradation products, low molecular weight (LMW) HA, has inflammatory properties and can decrease endothelial cell barrier function and induce expression of inflammatory mediators. In patients with ARDS, elevated levels of alveolar LMW HA have been associated with increased Lung Injury Score. Surprisingly, HMW HA has biologic properties opposite of LMW HA based primarily due to its molecular size. Therefore, investigators have previously studied the therapeutic use of exogenous administration of HMW HA in lung disorders. Despite promising pre-clinical data, a major limitation for the use of HMW HA for ARDS has remained the concern of giving an immunosuppressive therapy in patients with severe infection. In the current proposal, we hypothesize that administration of HMW HA will further restore major indices of ALI from severe bacterial pneumonia and/or sepsis in part through increased (1) antimicrobial activity and (2) through neutralization of inflammatory extracellular vesicles (EV) released during the exudative phase of ALI. In Aim 1, we will determine the therapeutic effects of HMW HA administration in established mouse models of severe bacterial pneumonia. We hypothesize that the mechanisms underlying the therapeutic effects of HMW HA will be due to increased antimicrobial activity of innate immune cells, binding of inflammatory EVs released early in the exudative phase of ALI, and through the restoration of the endothelial glycocalyx layer. To make the small pre-clinical animal studies more clinically relevant, in Aim 2, we will determine the therapeutic effects of HMW HA administration in an ex vivo perfused human lung injured with severe E.coli or Pseudomonas aeruginosa bacterial pneumonia. And to overcome some of the limitations of the perfused human lung such as a lack of the liver and spleen which are the major sites of HA degradation, in Aim 3, we will determine the therapeutic effects of HMW HA administration in a well-established ovine model of septic shock induced by smoke inhalation and Pseudomonas aeruginosa pneumonia. If successful, HMW HA, an inexpensive, non-immunogenic biologic already in use in clinical trials for other sterile inflammatory pulmonary disorders such as COPD, may prove to be a viable therapy for ARDS and/or sepsis.